Declarative memory permits an organism to bridge the past with the present, providing information about prior events that serves to inform present decisions and action. Declarative memory critically depends on the medial temporal lobe (MIL), which is composed of the hippocampal formation (dentate gyrus, fields of cornu Ammonis, and subiculum) and the surrounding entorhinal, perirhinal, and parahippocampal cortices. Though decades of research have aimed to characterize the role of MIL in declarative memory, fundamental questions remain regarding the functional contributions of specific MTL substructures. Recent advances in functional imaging have now made it possible to begin to address these questions in humans. The proposed research will use high-resolution functional MRI and anatomically-based analysis methods to delineate the role of specific MTL cortical and hippocampal subfields in declarative memory. The proposed experiments will test anatomically-informed theory-driven hypotheses regarding the nature of declarative memory and its dependence on MTL function. Expts 1-3 will examine novelty-encoding processes in the anterior/posterior and coronal axes of MTL, focusing on whether content-sensitive encoding effects are present within distinct MTL cortices and hippocampal subfields. Expts 4-9 will explore the function of MTL substructures and their interactions during declarative memory encoding and retrieval, focusing on decomposition of mechanisms that support conjunctive and item memory. Expts 10-12 will test hypotheses about the nature of MTL retrieval mechanisms signaling item familiarity and temporal recency, including their dependence on study- test perceptual similarity. Expts 13-14 will examine how hippocampal and MTL cortical encoding mechanisms that encode item and conjunctive memories are impacted by goal-directed attention, including attention-dependent enhancement and suppression of MTL responses. The basic knowledge to be gained from this programmatic effort to test theory-driven hypotheses of declarative memory and MTL substructure function promises to yield new insights into the nature of learning and memory impairments in clinical populations. Declarative memory deficits accompany a number of clinical conditions, including schizophrenia, mild cognitive impairment, and Alzheimer's disease. We will directly translate the obtained outcomes to inform our collaborative studies of MTL dysfunction in schizophrenia.